DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3 – 4, and 10 – 11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 recites the limitation "the plasma concentration" in lines 1 – 2 of the claim; however, independent claim 1, from which claim 3 depends, does not recite a limitation for “plasma concentration”. There is insufficient antecedent basis for this limitation in the claim.
Claim 10 recites the limitation "the concentration" in lines 1 – 2 of the claim; however, independent claim 8, from which claim 10 depends, does not recite a limitation for “concentration”. There is insufficient antecedent basis for this limitation in the claim.
Claim 4 recites, the method of claim 1, wherein the myotrope comprises omecamtiv mecarbil (OM), APD418 (beta3-AR antagonist), danicamtiv, levosimendan, or combinations thereof. Regarding claim 4, the use of parenthesis around beta3-AR antagonist, in the claim renders the claim indefinite because it is unclear whether the recitation within the parenthesis is a definition or a preferred embodiment. For example, the claim recites APD418 (beta3-AR antagonist) does the method require APD418 or any beta3-AR antagonist? As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of what myotrope can be used in the active step of method. Moreover the use of comprises within the claim is interpreted to include unrecited myotropes. Therefore, given the uncertainty around the terms within the parenthesis claim 4 is rejected under 35 U.S.C. 112(b).
Claim 11 recites, the method of claim 8, wherein the myotrope comprises omecamtiv mecarbil (OM), APD418 (beta3-AR antagonist), danicamtiv, levosimendan, or combinations thereof. Regarding claim 4, the use of parenthesis around beta3-AR antagonist, in the claim renders the claim indefinite because it is unclear whether the recitation within the parenthesis is a definition or a preferred embodiment. For example, the claim recites APD418 (beta3-AR antagonist) does the method require APD418 or any beta3-AR antagonist? As a consequence, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Specifically one of ordinary skill in the art would not be reasonably apprised of what myotrope can be used in the active step of method. Moreover the use of comprises within the claim is interpreted to include unrecited myotropes. Therefore, given the uncertainty around the terms within the parenthesis claim 11 is rejected under 35 U.S.C. 112(b).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, and 4 – 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Altenberger et. al. ((2014), Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial, European Journal of Heart Failure, 16, 898 – 906) and evidenced by Panat et. al. ((2012), Pulse Therapy: A Boon or Bane, Journal of Dental Sciences & Oral Rehabilitation, 1 – 3).
Regarding claims 1, and 4 – 7, Altenberger et. al. teach that advanced heart failure (AHF) is increasingly prevalent and is associated with high morbidity and mortality. See page 899 column 1 paragraph 1. See claim 1 limitation for a method for treating heart failure. Furthermore, Altenberger et. al. teach that evidence-based therapy with neurohormonal antagonists and CRT alleviates symptoms and reduces the risk of mortality in AHF. See page 899 column 1 paragraph 2. Additionally, Altenberger et. al. teach that although the rate of decline may be reduced, disease progression is only infrequently reversed, so that a sizeable proportion of patients with AHF remain highly symptomatic. See page 899 column 1 paragraph 2. Moreover, Altenberger et. al. teach that levosimendan causes haemodynamic improvements in patients with AHF. See page 899 column 1 paragraph 5. See claim 1 limitation for a method where a myotrope is administered. See claim 4 limitation for a method where the myotrope is levosimendan. Likewise, Altenberger et. al. teach that levosimendan pharmacological and haemodynamic properties, and the existence of an active metabolite that reaches peak plasma concentration 80–90 h after administration of the parent drug, make levosimendan attractive for pulsed applications in AHF. See page 899 column 1 paragraph 5. Thus, Altenberger et. al. teach a study comprising a 6-week treatment period and an 18-week follow-up period where, during the treatment period, patients underwent pulsed administration of four cycles of levosimendan at 2-week intervals. See page 899 column 2 paragraph 3. See claim 1 limitation for a method where the dosage scheme has an administration-withdrawal cycle. See claim 6 limitation for a method where the subject is a mammal. See claim 7 limitation for a method where the subject is human.
Moreover, Altenberger et. al. teach that in the study levosimendan was infused on an ambulatory basis for 6h at a dose of 0.2 μg/kg/min, without a bolus and the morning doses of diuretics were withheld on days of levosimendan administration. See page 899 column 2 paragraph 3. Furthermore, Altenberger et. al. teach that if symptomatic hypotension occurred or systolic blood pressure dropped below 80mmHg despite optimized fluid management, the dose of study medication was halved; if hypotension persisted, study medication was temporarily discontinued; and recommenced if considered appropriate by the treating physician. See page 899 column 2 paragraph 3. Additionally, Altenberger et. al. teach that secondary endpoint data suggest that, compared with placebo, four cycles of bi-weekly 6 h infusions of levosimendan may result in a reduction in risk of death, heart transplantation, or AHF after 24 weeks. See page 902 column 2 paragraph 1.
Regarding claim 1, limitation for a method for treating heart failure where the dosage scheme has an administration-withdrawal cycle; as taught above, Altenberger et. al. teach a study comprising a 6-week treatment period and an 18-week follow-up period where, during the treatment period, patients underwent pulsed administration of four cycles of levosimendan at 2-week intervals. As evidenced by Panat et. al., pulsed therapy is defined as the administration of a suprapharmacologic dose of a drug in an intermittent manner to enhance the therapeutic effect and reduce the side effects. See page 1 column 1 paragraph 1. Hence the teachings of prior art Altenberger et.al. for a method for treating heart failure in a human subject comprising administering a myotrope, that is levosimendan, in a pulsed administration where the levosimendan is intermittently administered anticipates claims 1, 4, 6, and 7 of the examined application. Thus, claims 1, 4, 6, and 7 are rejected under 35 U.S.C. 102(a)(1).
Regarding claims 5 limitation for a method wherein productive growth of a heart muscle in a subject; as taught above, prior art Altenberger et.al. does teach a method for treating heart failure in a human subject comprising administering a myotrope, that is levosimendan, in a pulsed administration where the levosimendan is intermittently administered. Hence, Altenberger et.al. teach every element required by claim 1 under its broadest reasonable interpretation; thus it would have been inherent that the intermittent administration of levosimendan would result in the productive growth of the heart muscle in the subject. Hence the teachings of prior art Altenberger et.al. for a method for treating heart failure in a human subject comprising administering a myotrope, that is levosimendan, in a pulsed administration where the levosimendan is intermittently administered anticipates claims 1, and 4 – 7 of the examined application. Thus, claims 1, and 4 – 7 are rejected under 35 U.S.C. 102(a)(1).
Claims 8, 11, and 14 – 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Altenberger et. al. ((2014), Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial, European Journal of Heart Failure, 16, 898 – 906) and evidenced by Panat et. al. ((2012), Pulse Therapy: A Boon or Bane, Journal of Dental Sciences & Oral Rehabilitation, 1 – 3).
Regarding claims 8, 11, and 14 – 15, Altenberger et. al. teach that advanced heart failure (AHF) is increasingly prevalent and is associated with high morbidity and mortality. See page 899 column 1 paragraph 1. Furthermore, Altenberger et. al. teach that evidence-based therapy with neurohormonal antagonists and CRT alleviates symptoms and reduces the risk of mortality in AHF. See page 899 column 1 paragraph 2. Additionally, Altenberger et. al. teach that although the rate of decline may be reduced, disease progression is only infrequently reversed, so that a sizeable proportion of patients with AHF remain highly symptomatic. See page 899 column 1 paragraph 2. Moreover, Altenberger et. al. teach that levosimendan causes haemodynamic improvements in patients with AHF. See page 899 column 1 paragraph 5. See claim 8 limitation for a method where a myotrope is administered. See claim 11 limitation for a method where the myotrope is levosimendan. Likewise, Altenberger et. al. teach that levosimendan pharmacological and haemodynamic properties, and the existence of an active metabolite that reaches peak plasma concentration 80–90 h after administration of the parent drug, make levosimendan attractive for pulsed applications in AHF. See page 899 column 1 paragraph 5. Thus, Altenberger et. al. teach a study comprising a 6-week treatment period and an 18-week follow-up period where, during the treatment period, patients underwent pulsed administration of four cycles of levosimendan at 2-week intervals. See page 899 column 2 paragraph 3. See claim 8 limitation for a method where the myotrope in intermittently contacting the heart muscle. See claim 13 limitation for a method where the heart muscle is the heart of the subject. See claim 14 limitation for a method where the subject is a mammal. See claim 15 limitation for a method where the subject is human.
Moreover, Altenberger et. al. teach that in the study levosimendan was infused on an ambulatory basis for 6h at a dose of 0.2 μg/kg/min, without a bolus and the morning doses of diuretics were withheld on days of levosimendan administration. See page 899 column 2 paragraph 3. Furthermore, Altenberger et. al. teach that if symptomatic hypotension occurred or systolic blood pressure dropped below 80mmHg despite optimized fluid management, the dose of study medication was halved; if hypotension persisted, study medication was temporarily discontinued; and recommenced if considered appropriate by the treating physician. See page 899 column 2 paragraph 3. Additionally, Altenberger et. al. teach that secondary endpoint data suggest that, compared with placebo, four cycles of bi-weekly 6 h infusions of levosimendan may result in a reduction in risk of death, heart transplantation, or AHF after 24 weeks. See page 902 column 2 paragraph 1.
Regarding claim 8 limitation for a method where the myotrope intermittently contacts the heart muscle; as taught above, Altenberger et. al. teach a study comprising a 6-week treatment period and an 18-week follow-up period where, during the treatment period, patients underwent pulsed administration of four cycles of levosimendan at 2-week intervals. Additionally, as evidenced by Panat et. al., pulsed therapy is defined as the administration of a suprapharmacologic dose of a drug in an intermittent manner to enhance the therapeutic effect and reduce the side effects. See page 1 column 1 paragraph 1. Moreover, the administration of levosimendan by IV allows for the systemic administration of the drug; thus one of ordinary skill in the art can envisage that the IV administration of levosimendan leads to the drug contacting the heart muscle.
Moreover, in regards to claim 8, limitation for a method causing productive growth of a heart muscle in a subject; as taught above, prior art Altenberger et.al. does teach a method for treating heart failure in a human subject comprising administering a myotrope, that is levosimendan, in a pulsed administration where the levosimendan is intermittently administered. Hence, Altenberger et.al. teach the required method steps as required by claim 8 under its broadest reasonable interpretation; thus it would have been inherent that the intermittent administration of levosimendan would result in the productive growth of the heart muscle in the subject. Thus, the teachings of prior art Altenberger et.al. comprising administering a myotrope, that is levosimendan, in a pulsed administration where the levosimendan is intermittently contacts the heart anticipates claim 8; thus, claims 8, 11, and 14 – 15 are rejected under 35 U.S.C. 102(a)(1).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 – 7 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication Number US 2020/0155547 to Honarpour et. al. (Honarpour’547; cited on the ISR form) in view of Altenberger et. al. ((2014), Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial, European Journal of Heart Failure, 16, 898 – 906) and evidenced by Panat et. al. ((2012), Pulse Therapy: A Boon or Bane, Journal of Dental Sciences & Oral Rehabilitation, 1 – 3).
Regarding claims 1 – 7, Honarpour’547 teach methods of treating a subject with heart failure comprising administering a cariad sarcomere activator (CSA). See page 1 paragraph 0007. See claim 1 limitation for a method of treating heart failure. Moreover, Honarpour’547 teach the administration of a cardiac sarcomere activator (CSA) at an initial dose, e.g., a starting dose, for an initial time period, and subsequently administering the CSA at a dose that is determined based on the subject's plasma concentration during or at the end of the initial time period. See page 1 paragraph 0006. See claim 3 limitation for a method where the plasma concentration of the myotrope in the subject cycles between above a first threshold concentration and below a second threshold concentration during the administration, wherein the first threshold concentration is equal to or higher than the second threshold concentration. Furthermore, Honarpour’547 teach embodiments where the CSA is omecamtiv mecarbil (OM), or levosimendan. See page 4 paragraphs 0030 and 0032 – 0033. See claim 4 limitation for a method where the myotrope comprises OM or levosimendan. Honarpour’547 teach embodiments where the subject in the method is a mammal and human. See page 4 paragraph 0025 – 0026. See claim 6 limitation for a method where the subject is a mammal. See claim 7 limitation for a method where the subject is a human. Additionally, Honarpour’547 teach embodiments where the CSA is administered to the subject once daily or twice daily. See page 10 paragraph 0077. See claim 2 limitation for a method wherein the myotrope is administered at a frequency of less than two doses per day.
In particular, Honarpour’547 teach in example 3 the assessment of cardiac myosin activator OM effects on cardiac function and structure. See page 17 paragraph 0161. Additionally, Honarpour’547 teach that patients at random received 25 mg oral omecamtiv mecarbil twice daily (fixed dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. Moreover, Honarpour’547 teach that changes in cardiac function and ventricular diameters were assessed. See page 17 paragraph 0164.
However, Honarpour’547 fails to teach a method where the method includes a dosage scheme with an administration-withdrawal cycle. See claim 1 limitation.
Nevertheless, Altenberger et. al. teach that advanced heart failure (AHF) is increasingly prevalent and is associated with high morbidity and mortality. See page 899 column 1 paragraph 1. Furthermore, Altenberger et. al. teach that evidence-based therapy with neurohormonal antagonists and CRT alleviates symptoms and reduces the risk of mortality in AHF. See page 899 column 1 paragraph 2. Altenberger et. al. teach that although the rate of decline may be reduced, disease progression is only infrequently reversed, so that a sizeable proportion of patients with AHF remain highly symptomatic. See page 899 column 1 paragraph 2. Altenberger et. al. teach that levosimendan causes haemodynamic improvements in patients with AHF. See page 899 column 1 paragraph 5. Altenberger et. al. teach that levosimendan pharmacological and haemodynamic properties, and the existence of an active metabolite that reaches peak plasma concentration 80–90 h after administration of the parent drug, make levosimendan attractive for pulsed applications in AHF. See page 899 column 1 paragraph 5. Thus, Altenberger et. al. teach a study comprising a 6-week treatment period and an 18-week follow-up period where, during the treatment period, patients underwent pulsed administration of four cycles of levosimendan at 2-week intervals. See page 899 column 2 paragraph 3. See claim 1 limitation for a method where the dosage scheme has an administration-withdrawal cycle.
Moreover, Altenberger et. al. teach that in the study levosimendan was infused on an ambulatory basis for 6h at a dose of 0.2 μg/kg/min, without a bolus and the morning doses of diuretics were withheld on days of levosimendan administration. See page 899 column 2 paragraph 3. Furthermore, Altenberger et. al. teach that if symptomatic hypotension occurred or systolic blood pressure dropped below 80mmHg despite optimized fluid management, the dose of study medication was halved; if hypotension persisted, study medication was temporarily discontinued; and recommenced if considered appropriate by the treating physician. See page 899 column 2 paragraph 3. Additionally, Altenberger et. al. teach that secondary endpoint data suggest that, compared with placebo, four cycles of bi-weekly 6 h infusions of levosimendan may result in a reduction in risk of death, heart transplantation, or AHF after 24 weeks. See page 902 column 2 paragraph 1.
Regarding claims 5 limitation for a method wherein productive growth of a heart muscle in a subject; as taught above, prior art Altenberger et.al. does teach a method for treating heart failure in a human subject comprising administering a myotrope, that is levosimendan, in a pulsed administration where the levosimendan is intermittently administered. Hence, the productive growth of the heart muscle in the subject would necessarily flow from the intermittent administration of levosimenden for the treatment of heart failure.
Regarding claim 1, limitation for a method for treating heart failure where the dosage scheme has an administration-withdrawal cycle; as taught above, Altenberger et. al. teach a study comprising a 6-week treatment period and an 18-week follow-up period where, during the treatment period, patients underwent pulsed administration of four cycles of levosimendan at 2-week intervals. As evidenced by Panat et. al., pulsed therapy is defined as the administration of a suprapharmacologic dose of a drug in an intermittent manner to enhance the therapeutic effect and reduce the side effects. See page 1 column 1 paragraph 1. Hence the teachings of prior art Altenberger et.al. for a method for treating heart failure in a human subject comprising administering a myotrope, that is levosimendan, in a pulsed administration where the levosimendan is intermittently administered.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Honarpour’547 for treating heart failure comprising administering OM or levosimendan in view of Altenberger et. al., that is to administer either OM or levosimendan in an administration-withdrawal cycle. One of ordinary skill in the art would have been motivated to make this modification because levosimendan causes haemodynamic improvements in patients with AHF. One of ordinary skill in the art would have had a reasonable expectation of success because the active metabolite reaches peak plasma concentration at 80–90 h after administration of levosimendan.
Claims 8 – 12, and 13 – 14 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication Number US 2020/0155547 to Honarpour et. al. (Honarpour’547; cited on the ISR form) in view of Altenberger et. al. ((2014), Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial, European Journal of Heart Failure, 16, 898 – 906) and evidenced by Panat et. al. ((2012), Pulse Therapy: A Boon or Bane, Journal of Dental Sciences & Oral Rehabilitation, 1 – 3).
Regarding claims 8 – 12, and 13 – 14, Honarpour’547 teach methods of treating a subject with heart failure comprising administering a cariad sarcomere activator (CSA). See page 1 paragraph 0007. Moreover, Honarpour’547 teach the administration of a cardiac sarcomere activator (CSA) at an initial dose, e.g., a starting dose, for an initial time period, and subsequently administering the CSA at a dose that is determined based on the subject's plasma concentration during or at the end of the initial time period. See page 1 paragraph 0006. See claim 10 limitation for a method where the plasma concentration of the myotrope in the subject cycles between above a first threshold concentration and below a second threshold concentration during the administration, wherein the first threshold concentration is equal to or higher than the second threshold concentration. Furthermore, Honarpour’547 teach embodiments where the CSA is omecamtiv mecarbil (OM), or levosimendan. See page 4 paragraphs 0030 and 0032 – 0033. See claim 11 limitation for a method where the myotrope comprises OM or levosimendan. Honarpour’547 teach embodiments where the subject in the method is a mammal and human. See page 4 paragraph 0025 – 0026. See claim 14 limitation for a method where the subject is a mammal. See claim 15 limitation for a method where the subject is a human. Additionally, Honarpour’547 teach embodiments where the CSA is administered to the subject once daily or twice daily. See page 10 paragraph 0077. See claim 9 limitation for a method wherein the myotrope is administered at a frequency of less than two doses per day.
In particular, Honarpour’547 teach in example 3 the assessment of cardiac myosin activator OM effects on cardiac function and structure. See page 17 paragraph 0161. Additionally, Honarpour’547 teach that patients at random received 25 mg oral omecamtiv mecarbil twice daily (fixed dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. Moreover, Honarpour’547 teach that changes in cardiac function and ventricular diameters were assessed. See page 17 paragraph 0164.
However, Honarpour’547 fails to teach a method where the method where the myotrope intermittently contacts the heart muscle or a method which causes the productive growth of a heart muscle. See claim 8 limitation.
Nevertheless, Altenberger et. al. teach that advanced heart failure (AHF) is increasingly prevalent and is associated with high morbidity and mortality. See page 899 column 1 paragraph 1. Furthermore, Altenberger et. al. teach that evidence-based therapy with neurohormonal antagonists and CRT alleviates symptoms and reduces the risk of mortality in AHF. See page 899 column 1 paragraph 2. Additionally, Altenberger et. al. teach that although the rate of decline may be reduced, disease progression is only infrequently reversed, so that a sizeable proportion of patients with AHF remain highly symptomatic. See page 899 column 1 paragraph 2. Moreover, Altenberger et. al. teach that levosimendan causes haemodynamic improvements in patients with AHF. See page 899 column 1 paragraph 5. See claim 8 limitation for a method where a myotrope is administered. See claim 11 limitation for a method where the myotrope is levosimendan. Likewise, Altenberger et. al. teach that levosimendan pharmacological and haemodynamic properties, and the existence of an active metabolite that reaches peak plasma concentration 80–90 h after administration of the parent drug, make levosimendan attractive for pulsed applications in AHF. See page 899 column 1 paragraph 5. Thus, Altenberger et. al. teach a study comprising a 6-week treatment period and an 18-week follow-up period where, during the treatment period, patients underwent pulsed administration of four cycles of levosimendan at 2-week intervals. See page 899 column 2 paragraph 3. See claim 8 limitation for a method where the myotrope in intermittently contacting the heart muscle. See claim 13 limitation for a method where the heart muscle is the heart of the subject. See claim 14 limitation for a method where the subject is a mammal. See claim 15 limitation for a method where the subject is human.
Moreover, Altenberger et. al. teach that in the study levosimendan was infused on an ambulatory basis for 6h at a dose of 0.2 μg/kg/min, without a bolus and the morning doses of diuretics were withheld on days of levosimendan administration. See page 899 column 2 paragraph 3. Furthermore, Altenberger et. al. teach that if symptomatic hypotension occurred or systolic blood pressure dropped below 80mmHg despite optimized fluid management, the dose of study medication was halved; if hypotension persisted, study medication was temporarily discontinued; and recommenced if considered appropriate by the treating physician. See page 899 column 2 paragraph 3. Additionally, Altenberger et. al. teach that secondary endpoint data suggest that, compared with placebo, four cycles of bi-weekly 6 h infusions of levosimendan may result in a reduction in risk of death, heart transplantation, or AHF after 24 weeks. See page 902 column 2 paragraph 1.
Regarding claim 8 limitation for a method where the myotrope intermittently contacts the heart muscle; as taught above, Altenberger et. al. teach a study comprising a 6-week treatment period and an 18-week follow-up period where, during the treatment period, patients underwent pulsed administration of four cycles of levosimendan at 2-week intervals. Additionally, as evidenced by Panat et. al., pulsed therapy is defined as the administration of a suprapharmacologic dose of a drug in an intermittent manner to enhance the therapeutic effect and reduce the side effects. See page 1 column 1 paragraph 1. Moreover, the administration of levosimendan by IV allows for the systemic administration of the drug; thus it would have been obvious to one of ordinary skill in the art that the IV administration of levosimendan leads to the drug contacting the heart muscle.
Moreover, in regards to claim 8, limitation for a method causing productive growth of a heart muscle in a subject; as taught above, prior art Altenberger et.al. does teach a method for treating heart failure in a human subject comprising administering a myotrope, that is levosimendan, in a pulsed administration where the levosimendan is intermittently administered. Hence, the productive growth of the heart muscle in the subject would necessarily flow from the intermittent administration of levosimenden for the treatment of heart failure.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Honarpour’547 for treating heart failure comprising administering OM or levosimendan in view of Altenberger et. al., that is to intermittently administer either OM or levosimendan for a method that causes productive growth of a heart muscle. One of ordinary skill in the art would have been motivated to make this modification because levosimendan causes haemodynamic improvements in patients with AHF. One of ordinary skill in the art would have had a reasonable expectation of success because the active metabolite reaches peak plasma concentration at 80–90 h after administration of levosimendan.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent Application Publication Number US 2020/0155547 to Honarpour et. al. (Honarpour’547; cited on the ISR form), Altenberger et. al. ((2014), Efficacy and safety of the pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep) study: a multicentre randomized trial, European Journal of Heart Failure, 16, 898 – 906) and evidenced by Panat et. al. ((2012), Pulse Therapy: A Boon or Bane, Journal of Dental Sciences & Oral Rehabilitation, 1 – 3), as applied to claim 8 – 12, and 13 – 14, above, and further in view of Greenberg et. al. ((2018), Genetic and Tissue Engineering Approaches to Modeling the Mechanics of Human Heart Failure for Drug Discovery, Front. Cardiovasc. Med., 5, 1 – 12).
The teachings of Honarpour’547 and Altenberger et. al. as they relate to claim 8, from which claim 12 depends, are given previously in this office action and are fully incorporated here.
However, the prior art of Honarpour’547 and Altenberger et. al. fail to teach a method where the heart muscle is in an engineered heart tissue. See claim 12.
Nevertheless, Greenberg et. al. teach that heart failure (HF) is the leading cause of death in the United States, accounting for 1 in 9 deaths that occur each year and over $30 billion in annual health care costs. See page 1 paragraph 1. Greenberg et. al. teach that even with the best treatments available, there are high rates of mortality and morbidity with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) partly due to our lack of mechanistic understanding of the disease pathogenesis. See page 2 column 1 paragraph 1. Moreover, Greenberg et. al. teach that another reason for the high rates of mortality and morbidity with both HFrEF and HFpEF is the lack of an appropriate in vitro model system that can recapitulate relevant aspects of cardiac mechanics with sufficient throughput for drug discovery. See page 2 column 1 paragraph 1. Additionally, Greenberg et. al. teach that the human heart has a complex three-dimensional structure composed of many cell types including cardiomyocytes, fibroblasts, macrophages, and endothelial cells. See page 3 column 2 paragraph 2.
Likewise, Greenberg et. al. teach that the cardiomyocytes interact with the other cell types, and these other cells can modulate the contractile and electrophysiological properties of cardiomyocytes. See page 3 column 2 paragraph 2. Thus, Greenberg et. al. teach that to recapitulate many of these aspects of cardiac functions in vitro, 3D engineered heart tissues (EHT) were first created more than two decades ago using cardiomyocytes isolated from chicken embryos. See page 3 column 2 paragraph 3.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the method of Honarpour’547 for treating heart failure comprising administering OM or levosimendan in view of Altenberger et. al., that is to intermittently administer either OM or levosimendan for a method that causes productive growth of a heart muscle and in further view of Greenberg et. al. to use engineered heart tissue. One of ordinary skill in the art would have been motivated to make this modification to safely study cardiac mechanics during drug discovery. One of ordinary skill in the art would have had a reasonable expectation of success because 3D engineered heart tissues (EHT) were well established at the time because EHT were first created more than two decades ago using cardiomyocytes isolated from chicken embryos. Thus one of ordinary skill in the would have had a reasonable expectation of success because EHTs safely recapitulate relevant aspects of cardiac mechanics during drug discovery such as cardiomyocytes interact with the other cell types.
Conclusion
Claims 1 – 15 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAWANNA S WHITE whose telephone number is (703)756-4687. The examiner can normally be reached 7:00 am - 5:00 pm [EST] M - Th.
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Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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